Recombinant α1-microglobulin (A1M) is proposed as a protector during 177Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of 177Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after 177Lu-octreotate and/or A1M administration. Mice were injected with 177Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on 177Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the 177Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to 177Lu-octreotate alone or together with A1M. Combining 177Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied.

α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.

The lipocalin proteins are a large family of small extracellular proteins that demonstrate significant heterogeneity in sequence similarity and have highly conserved crystal structures. They have a variety of functions, including acting as carrier proteins, transporting retinol, participating in olfaction, and synthesizing prostaglandins. Importantly, they also play a critical role in human diseases, including cancer. Additionally, they are involved in regulating cellular homeostasis and immune response and dispensing various compounds. This comprehensive review provides information on the lipocalin family, including their structure, functions, and implications in various diseases. It focuses on selective important human lipocalin proteins, such as lipocalin 2 (LCN2), retinol binding protein 4 (RBP4), prostaglandin D2 synthase (PTGDS), and α1-microglobulin (A1M).

α1-Microglobulin (A1M) is an antioxidant found in all vertebrates, including humans. It has enzymatic reductase activity and can scavenge radicals and bind free heme groups. Infused recombinant A1M accumulates in the kidneys and has therefore been successful in protecting kidney injuries in different animal models. In this review, we focus on A1M as a radioprotector of the kidneys during peptide receptor radionuclide/radioligand therapy (PRRT/RLT). Patients with, e.g., neuroendocrine tumors or castration resistant prostate cancer can be treated by administration of radiolabeled small molecules which target and therefore enable the irradiation and killing of cancer cells through specific receptor interaction. The treatment is not curative, and kidney toxicity has been reported as a side effect since the small, radiolabeled substances are retained and excreted through the kidneys. In recent studies, A1M was shown to have radioprotective effects on cell cultures as well as having a similar biodistribution as the somatostatin analogue peptide 177Lu-DOTATATE after intravenous infusion in mice. Therefore, several animal studies were conducted to investigate the in vivo radioprotective potential of A1M towards kidneys. The results of these studies demonstrated that A1M co-infusion yielded protection against kidney toxicity and improved overall survival in mouse models. Moreover, two different mouse studies reported that A1M did not interfere with tumor treatment itself. Here, we give an overview of radionuclide therapy, the A1M physiology and the results from the radioprotector studies of the protein.

Peptide receptor radionuclide therapy (PRRT) has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α₁-microglobulin (A1M) is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.

Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.